Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
Dyck
Brian
B
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
Tamiya
Junko
J
Jovic
Florence
F
Pick
Rebecca R
RR
Bradbury
Margaret J
MJ
O'Brien
Julie
J
Wen
Jenny
J
Johns
Michael
M
Madan
Ajay
A
Fleck
Beth A
BA
Foster
Alan C
AC
Li
Binfeng
B
Zhang
Mingzhu
M
Tran
Joe A
JA
Vickers
Troy
T
Grey
Jonathan
J
Saunders
John
J
Chen
Chen
C
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D000078764:Milnacipran; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013127:Spinal Nerves / Q000473:pathology / Q000601:surgery; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D000078764:Milnacipran; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors